Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Changzhou maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213000, China.
Int J Biol Sci. 2022 Aug 29;18(14):5539-5553. doi: 10.7150/ijbs.71809. eCollection 2022.
Overcoming energy stress is a critical step for cells in solid tumors. Under this stress microenvironment, cancer cells significantly alter their energy metabolism to maintain cell survival and even metastasis. Our previous studies have shown that thioredoxin-1 (Trx-1) expression is increased in colorectal cancer (CRC) and promotes cell proliferation. However, the exact role and mechanism of how Trx-1 is involved in energy stress are still unknown. Here, we observed that glucose deprivation of CRC cells led to cell death and promoted the migration and invasion, accompanied by upregulation of Trx-1. Increased Trx-1 supported CRC cell survival under glucose deprivation. Whereas knockdown of Trx-1 sensitized CRC cells to glucose deprivation-induced cell death and reversed glucose deprivation-induced migration, invasion, and epithelial-mesenchymal transition (EMT). Furthermore, we identified glucose-6-phosphate dehydrogenase (G6PD) interacting with Trx-1 by HuPortTM human protein chip, co-IP and co-localization. Trx-1 promoted G6PD protein expression and activity under glucose deprivation, thereby increasing nicotinamide adenine dinucleotide phosphate (NADPH) generation. Moreover, G6PD knockdown sensitized CRC cells to glucose deprivation-induced cell death and suppressed glucose deprivation-induced migration, invasion, and EMT. Inhibition of Trx-1 and G6PD, together with inhibition of glycolysis using 2-deoxy-D-glucose (2DG), resulted in significant anti-tumor effects in CRC xenografts . These findings demonstrate a novel mechanism and may represent a new effective therapeutic regimen for CRC.
克服能量应激是实体瘤细胞的关键步骤。在这种应激微环境下，癌细胞会显著改变其能量代谢以维持细胞存活，甚至促进转移。我们之前的研究表明，硫氧还蛋白-1（Trx-1）在结直肠癌（CRC）中表达增加，并促进细胞增殖。然而，Trx-1 如何参与能量应激的确切作用和机制仍不清楚。在这里，我们观察到 CRC 细胞的葡萄糖剥夺导致细胞死亡，并促进迁移和侵袭，同时 Trx-1 上调。增加的 Trx-1 支持 CRC 细胞在葡萄糖剥夺下的存活。而 Trx-1 的敲低使 CRC 细胞对葡萄糖剥夺诱导的细胞死亡敏感，并逆转葡萄糖剥夺诱导的迁移、侵袭和上皮-间充质转化（EMT）。此外，我们通过 HuPortTM 人类蛋白质芯片、共免疫沉淀和共定位鉴定了与 Trx-1 相互作用的葡萄糖-6-磷酸脱氢酶（G6PD）。Trx-1 在葡萄糖剥夺下促进 G6PD 蛋白表达和活性，从而增加烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的产生。此外，G6PD 的敲低使 CRC 细胞对葡萄糖剥夺诱导的细胞死亡敏感，并抑制葡萄糖剥夺诱导的迁移、侵袭和 EMT。抑制 Trx-1 和 G6PD ，并联合使用 2-脱氧-D-葡萄糖（2DG）抑制糖酵解，在 CRC 异种移植中产生了显著的抗肿瘤作用。这些发现揭示了一种新的机制，并可能为 CRC 提供一种新的有效治疗方案。
